Stepwise Deletions of PolyA Sequences in Mismatch Repair-Deficient Colorectal Cancers

PolyA simple repeat sequence deletions are common in tumors with microsatellite instability (MSI+). Such deletions occur one base at a time in DNA mismatch repair (MMR)-deficient yeast suggesting larger deletions in human MSI+ tumors represent multiple sequential stepwise losses. Sum total deletions in four polyA repeats were variable (between −17 to −45 bp) in 20 sporadic MSI+ colorectal cancers. Progressive but less extensive total deletions (maximum of −12 bp) occurred in similar polyA sequences in MMR-deficient mice (mlh1−/−) up to 478 days old. PolyA repeat lengths were relatively stable but already shortened in the MMR-deficient cell line HCT116. A transgene with 26 A’s transfected into HCT116 shortened an average of 3.8 bases pairs after 469 days in culture, less than average deletions of BAT25 (−5.3) or BAT26 (−9.0) in MSI+ cancers. These findings further suggest that extensive polyA deletions common in MSI+ tumors likely reflect multiple stepwise smaller deletions that accumulate more than hundreds of divisions after loss of MMR.